Edg-1 was cloned as an novel immediate-early response gene induced following phorbol ester stimulation of human umbilical vein endothelial cell differentiation. The deduced amino acid sequence of the edg-1 protein suggest that it is a seven-pass transmembrane receptor. The edg-1 ligand is currently unknown and so edg-1 is classified as an orphan receptor. Edg-1 couples to the Gi family of polypeptides and initiates sustained activation the mitogen activated protein kinase pathway. Sustained activation of the MAP kinase pathway is required for cellular differentiation in PC-12 neuronal cells and morphologic differentiation in Dictyostelium. Edg-1 overexpression results in morphologic differentiation of HEK293 cells by suppressing cell-matrix adhesion, upregulating E- and P-cadherins and inducing cell-cell adhesion. These findings support the central hypothesis of this proposal which is that in vascular endothelial cells edg-1 signaling regulates the morphogenetic differentiation phase of the angiogenic response. The objective of this proposal is to define the signaling pathways involved in this morphogenetic differentiation, as well as definition of the phenotype of the edg-1-induced differentiated state.